U.S. patent number 5,747,069 [Application Number 08/592,307] was granted by the patent office on 1998-05-05 for percutaneously absorbable preparation.
This patent grant is currently assigned to Fujisawa Pharmaceutical Co., Ltd.. Invention is credited to Sotoo Asakura, Takehisa Hata, Kazutake Kado, Sumihisa Kimura, Yoshiko Ohishi.
United States Patent |
5,747,069 |
Asakura , et al. |
May 5, 1998 |
Percutaneously absorbable preparation
Abstract
A percutaneously absorbable preparation containing a drug and a
percutaneous absorption accelerator comprising a monoglyceride and
a fatty acid.
Inventors: |
Asakura; Sotoo (Kyoto,
JP), Kimura; Sumihisa (Kawanishi, JP),
Kado; Kazutake (Toyonaka, JP), Ohishi; Yoshiko
(Kobe, JP), Hata; Takehisa (Nagaokakyo,
JP) |
Assignee: |
Fujisawa Pharmaceutical Co.,
Ltd. (Osaka, JP)
|
Family
ID: |
26510724 |
Appl.
No.: |
08/592,307 |
Filed: |
March 15, 1996 |
PCT
Filed: |
August 04, 1994 |
PCT No.: |
PCT/JP94/01282 |
371
Date: |
March 15, 1996 |
102(e)
Date: |
March 15, 1996 |
PCT
Pub. No.: |
WO95/04551 |
PCT
Pub. Date: |
February 16, 1995 |
Foreign Application Priority Data
|
|
|
|
|
Aug 10, 1993 [JP] |
|
|
5-198014 |
Dec 16, 1993 [JP] |
|
|
5-316319 |
|
Current U.S.
Class: |
424/484; 514/414;
514/469; 514/944; 514/183 |
Current CPC
Class: |
A61K
47/12 (20130101); A61K 38/05 (20130101); A61K
9/0014 (20130101); A61K 47/14 (20130101); A61K
38/12 (20130101); Y10S 514/944 (20130101) |
Current International
Class: |
A61K
38/05 (20060101); A61K 38/12 (20060101); A61K
47/14 (20060101); A61K 47/12 (20060101); A61K
009/06 () |
Field of
Search: |
;424/401,484
;514/183,414,469,944,969 |
Foreign Patent Documents
Other References
Primary Examiner: Venkat; Jyothsan
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier
& Neustadt, P.C.
Claims
What is claimed is:
1. A percutaneously absorbable pharmaceutical composition,
comprising:
1) a drug selected from the group consisting of those with the
formulae: ##STR5## 2) a percutaneously absorption accelerator,
comprising: a) a monoglyceride selected from the group consisting
of monocaprin, monolaurin, monomyristin, monopalmitin, monostearin
and monoolein; and
b) a fatty acid selected from the group consisting of capric acid,
lauric acid, myristic acid, palmitic acid and stearic acid.
2. The percutaneously absorbable pharmaceutical composition of
claim 1, wherein said drug has the formula: ##STR6##
3. The percutaneously absorbable pharmaceutical composition of
claim 1, wherein said drug has the formula: ##STR7##
4. The percutaneously absorbable pharmaceutical composition of
claim 1, wherein said drug has the formula: ##STR8##
5. The percutaneously absorbable pharmaceutical composition of
claim 1, wherein said drug has the formula: ##STR9##
6. The percutaneously absorbable pharmaceutical composition of
claim 1, wherein said monoglyceride is selected from the group
consisting of monocaprin, monolaurin and monoolein.
7. The percutaneously absorbable pharmaceutical composition of
claim 1, wherein said fatty acid is stearic acid.
8. The percutaneously absorbable pharmaceutical composition of
claim 1, which further comprises an excipient, coloring agent or
solubilizer.
9. The percentaneously absorbable pharmaceutical composition of
claim 8, wherein said solubilizer is selected from the group
consisting of propylene glycol, polyethylene glycol, glycerin,
ethyl alcohol, isopropyl alcohol, isopropyl myristate, diethyl
sebacate, diisopropyl adipate and propylene carbonate.
10. The percutaneously absorbable pharmaceutical composition of
claim 1, which is in a form of an ointment, cream, gel, plaster or
lotion.
Description
TECHNICAL FIELD
This application is a 371 of PCT/JP94/01282 filed Aug. 4, 1994.
This invention relates to a percutaneously absorbable preparation
containing a drug and a percutaneous absorption accelerator
comprising a monoglyceride and a fatty acid.
More particularly, this invention relates to a percutaneously
absorbable preparation containing a monoglyceride as well as a
fatty acid for enhanced cutaneous penetration of an insoluble
(insoluble or sparingly soluble in water) drug.
BACKGROUND
For the purpose of improving the percutaneous absorption of an
insoluble drug, it is common practice to employ a solubilizer such
as Polyethylene Glycol 400 or propylene glycol.
It is also known that monoglycerides of medium-chain fatty acids
assist in percutaneous absorption. For example, JP Kokai 63-227520
employs monolaurin, that is 1-monolauroylrac-glycerol, as a
percutaneous absorption accelerator.
However, the problem remains that even the use of cutaneous
penetration aids such as said solubilizers and monoglycerides of
medium-length fatty acids generally does not insure a sufficient
percutaneous delivery of drug which are inherently more or less
insoluble in water.
There accordingly exists a demand for the development of dosage
forms providing for still improved percutaneous absorption.
DISCLOSURE OF INVENTION
After much research for solving the above problem and even to their
own surprise, the inventors of this invention discovered that a
dramatic enhancement of cutaneous penetration can be achieved by
causing a fatty acid to be present in conjunction with a
monoglyceride and have perfected this invention.
This invention is now described in further detail.
The percutaneously absorbable preparation of this invention is
characterized by containing a drug and a percutaneous absorption
accelerator comprising a monoglyceride and a fatty acid.
The preferred monoglyceride for use in this preparation can be
selected from among those monoglycerides which are conventionally
employed in the pharmaceutical field, thus including glycerides of
medium-chain or long-chain fatty acids, whether saturated or
unsaturated, typically monocaprin, monolaurin, monomyristin,
monopalmitin, monostearin, monoolein, etc., and mixtures thereof.
In particular, glycerides of saturated or unsaturated fatty acids
containing 10 to 20 carbon atoms are preferred, and monocaprin,
monolaurin and monoolein are especially useful.
As preferred examples of the fatty acid for use in this invention,
those fatty acids which are conventionally employed in the
pharmaceutical field can be mentioned. Typically, medium-chain and
long-chain fatty acids, whether saturated or unsaturated, such as
capric acid, lauric acid, myristic acid, palmitic acid, stearic
acid, etc., and mixtures thereof can be mentioned. Particularly
preferred are saturated C.sub.12 -C.sub.18 fatty acids, among which
stearic acid is especially useful.
Where necessary, the percutaneously absorbable preparation of this
invention may further contain the common additives which are
generally used in the formulation of drug products, typically an
excipient, a coloring agent, a solubilizer, and so on.
As to the solubilizer mentioned above, in particular, hydrophilic
solvents such as polyhydric alcohols, e.g. propylene glycol,
polyethylene glycol, glycerin, etc., and monohydric alcohols, e.g.
ethyl alcohol, isopropyl alcohol, etc., including mixtures thereof
can be employed.
Furthermore, long-chain or cyclic esters such as isopropyl
myristate, diethyl sebacate, diisopropyl adipate, propylene
carbonate, etc. can also be mentioned.
The percutaneously absorbable preparation of this invention can be
provided in the form of an ordinary ointment. The ointment base
that can be used includes vegetable or animal waxes (e.g. bleached
beeswax, carnauba wax, beeswax, etc.), paraffins (e.g. paraffin,
liquid paraffin, etc.), and petrolatums (e.g. white petrolatum
etc.), among others. These bases can be used in the form of a
mixture. Moreover, this preparation can be provided in the form of
an ordinary cream, gel, plaster or lotion as well.
The proportion of said percutaneous absorption accelerator in the
dosage form is 1-50 weight % and preferably 5-20 weight %.
The percutaneously absorbable preparation of this invention can be
manufactured by, typically, dissolving a drug in propylene glycol
or the like and mixing the solution with said monoglyceride and
fatty acid, where necessary followed by addition of conventional
additives.
While the drug that can be used in this invention is not
particularly limited in kind but includes a broad variety of
substances, there can typically be mentioned therapeutic agents for
infectious diseases, such as antibiotics and antiviral agents,
antiasthmatics, analgesics, antiinflammatory agents, antianginal
agents, and neuroleptic agents, among other drugs. Particularly
suitable, among them, are the compounds described in the following
literature and known to have such pharmacologic activities as
antitachykinin activity, particularly substance P-antagonizing
activity, neurokinin A-antagonizing activity and neurokinin
B-antagonizing activity, and be particularly useful for the
treatment or prevention of pain.
The compound described in JP Kokai 4-210996: ##STR1##
The compound described in JP Kokai 2-204499: ##STR2## The compound
described in WO 93/21215: ##STR3##
Another preferred example is the following compound which is
described in JP Kokai 61-148181 as being of value as an
immunosuppressant. ##STR4##
EXAMPLES
The following examples are further illustrative of this
invention.
Example b 1
Compound (A) (1 part by weight) is added to propylene glycol (5
parts by weight) and the mixture is heated to 75 C. for
dissolution. To this propylene glycol solution of compound (1) are
added monolaurin (10 parts by weight), stearic acid (1 part by
weight), bleached beeswax (3 parts by weight), liquid paraffin (40
parts by weight), and white petrolatum (40 parts by weight) and the
mixture is heated at 75 C. for dissolution. The above mixture is
placed in an agitator-homomixer (homomixer: 5000 rpm, paddle mixer
30 rpm, agitation time 10 min.) set to an internal temperature of
75.+-.2 C. and agitated. Then, under agitation at a homomixer speed
of 3000 rpm and a paddle mixer speed of 30 rpm, the internal
temperature of the machine is lowered to 45.+-.2 C. Thereafter, the
agitation is continued by driving the paddle mixer alone at a speed
of 18 rpm until the temperature level of 40.+-.2 C. has been
reached to complete preparation of an ointment.
Example 2
Ointments are manufactured according to the following recipes in
otherwise the same manner as Example 1.
______________________________________ (1) Compound (A) 1 part by
weight Propylene glycol 5 parts by weight Monolaurin 10 parts by
weight Stearic acid 2 parts by weight Bleached beeswax 6 parts by
weight Liquid paraffin 35 parts by weight White petrolatum 42 parts
by weight 101 parts by weight (2) Compound (A) 1 part by weight
Propylene glycol 5 parts by weight Monoolein 10 parts by weight
Stearic acid 2 parts by weight Bleached beeswax 6 parts by weight
Liquid paraffin 35 parts by weight White petrolatum 42 parts by
weight 101 parts by weight (3) Compound (A) 1 part by weight
Propylene glycol 5 parts by weight Monocaprin 10 parts by weight
Stearic acid 2 parts by weight Bleached beeswax 6 parts by weight
Liquid paraffin 35 parts by weight White petrolatum 42 parts by
weight 101 parts by weight (4) Compound (B) 1 part by weight
Propylene glycol 5 parts by weight Monolaurin 10 parts by weight
Stearic acid 2 parts by weight Bleached beeswax 6 parts by weight
Liquid paraffin 35 parts by weight White petrolatum 42 parts by
weight 101 parts by weight (5) Compound (B) 1 part by weight
Propylene glycol 5 parts by weight Monoolein 10 parts by weight
Stearic acid 2 parts by weight Bleached beeswax 6 parts by weight
Liquid paraffin 35 parts by weight White petrolatum 42 parts by
weight 101 parts by weight (6) Compound (B) 1 part by weight
Propylene glycol 5 parts by weight Monocaprin 10 parts by weight
Stearic acid 2 parts by weight Bleached beeswax 6 parts by weight
Liquid paraffin 35 parts by weight White petrolatum 42 parts by
weight 101 parts by weight (7) Compound (C) 1 part by weight
Propylene glycol 5 parts by weight Monolaurin 10 parts by weight
Stearic acid 2 parts by weight Bleached beeswax 6 parts by weight
Liquid paraffin 35 parts by weight White petrolatum 42 parts by
weight 101 parts by weight (8) Compound (C) 1 part by weight
Propylene glycol 5 parts by weight Monoolein 10 parts by weight
Stearic acid 2 parts by weight Bleached beeswax 6 parts by weight
Liquid paraffin 35 parts by weight White petrolatum 42 parts by
weight 101 parts by weight (9) Compound (C) 1 part by weight
Propylene glycol 5 parts by weight Monocaprin 10 parts by weight
Stearic acid 2 parts by weight Bleached beeswax 6 parts by weight
Liquid paraffin 35 parts by weight White petrolatum 42 parts by
weight 101 parts by weight (10) Compound (D) 1 part by weight
Propylene glycol 5 parts by weight Monolaurin 10 parts by weight
Stearic acid 2 parts by weight Bleached beeswax 6 parts by weight
Liquid paraffin 35 parts by weight White petrolatum 42 parts by
weight 101 parts by weight (11) Compound (D) 1 parts by weight
Propylene glycol 5 parts by weight Monoolein 10 parts by weight
Stearic acid 2 parts by weight Bleached beeswax 6 parts by weight
Liquid paraffin 35 parts by weight White petrolatum 42 parts by
weight 101 parts by weight (12) Compound (D) 1 part by weight
Propylene glycol 5 parts by weight Monocaprin 10 parts by weight
Stearic acid 2 parts by weight Bleached beeswax 6 parts by weight
Liquid paraffin 35 parts by weight White petrolatum 42 parts by
weight 101 parts by weight
______________________________________
Reference Example 1
Ointments are prepared according to the following recipes in
otherwise the same manner as Example 1.
______________________________________ (1) Compound (A) 1 part by
weight Propylene glycol 5 parts by weight Bleached beeswax 10 parts
by weight Liquid paraffin 35 parts by weight White petrolatum 49
parts by weight 100 parts by weight (2) Compound (A) 1 part by
weight Propylene glycol 5 parts by weight Monolaurin 10 parts by
weight Bleached beeswax 3 parts by weight Liquid paraffin 42 parts
by weight White petrolatum 39 parts by weight 100 parts by weight
(3) Compound (A) 1 part by weight Propylene glycol 5 parts by
weight Monoolein 10 parts by weight Bleached beeswax 8 parts by
weight Liquid paraffin 37 parts by weight White petrolatum 39 parts
by weight 100 parts by weight
______________________________________
EFFECTS OF INVENTION
The cutaneous penetration of drugs could be enhanced with the
percutaneously absorbable preparation of this invention.
The following percutaneous absorption test data are presented as
evidence for the beneficial effect that accrues from the use of the
preparation of this invention.
(I) Test dosage forms
(a) The dosage form obtained in Reference Example 1-(1)
(b) The dosage form obtained in Reference Example 1-(2)
(c) The dosage form obtained in Reference Example 1-(3)
(d) The dosage form obtained in Example 1
(e) The dosage form obtained in Example 2-(1)
(II) Method
The abdomen of rats (SD strain, 7-8 weeks old, average body weight
ca. 250 g) was clipped of hairs and after an interval of 24 hours,
100 mg of the test dosage form was applied to a 10 cm square area
of the abdominal skin. Blood was drawn serially from the subclavian
vein and centrifuged to separate the plasma and the plasma drug
concentration was determined by high performance liquid
chromatography.
(III) Results
The areas under the plasma concentration-time curves
(AUC.sub.0-24)are shown in the following table.
______________________________________ Test dosage form
AUC.sub.0-24 (ng hr/ml) ______________________________________ (a)
0 (b) 215 (c) 118 (d) 1341 (e) 1656
______________________________________
It is apparent from the above percutaneous absorption test data
that the dosage forms (d) and (e) of this invention have been
remarkably improved in the degree of cutaneous penetration of the
active substance as compared with the monoglyceride-free dosage
form (a). It is also apparent from comparison with the dosage forms
(b) and (c) that causing a fatty acid to be present in conjunction
with a monoglyceride leads to enhanced cutaneous penetration.
Therefore, the percutaneously absorbable preparation of this
invention is remarkably useful.
* * * * *